The investigational HIV integrase inhibitor GSK1265744 was well tolerated with no notable safety concerns in a meta-analysis of 8 studies testing the drug as either a pill or a long-acting injection, researchers reported at the recent 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) in Denver.

GSK1265744 (or GSK744 for short), being developed by GlaxoSmithKline, has shown robust antiviral activity in clinical trials to date. It is now in Phase 2b trials. While another well-tolerated once-daily integrase inhibitor would be a welcome addition to the antiretroviral armamentarium, a more ground-breaking application would be a once-monthly injection, which potentially could be used for simplified maintenance therapy or pre-exposure prophylaxis (PrEP).

At the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this past summer, William Spreen from GlaxoSmithKline reported that an injected nanosuspension formulation of GSK744plus TMC278-LA, a long-acting formulation of Janssen's NNRTI rilpivirine (Edurant) was safe and generally well-tolerated in healthy, HIV negative volunteers.

Of these studies, 6 looked at oral tablet or suspension formulations administered to HIV negative healthy volunteers or HIV positive patients for up to 14 days. Participants received single or multiple doses ranging from 5 to 50 mg.

Another 2 studies looked at the LAP formulation in healthy volunteers receiving a single dose or repeat doses given as either 4 monthly injections or 2 quarterly injections (this includes people receiving the GSK744/TMC278 combination). Participants received intramuscular injections ranging from 100 to 800 mg or subcutaneous injections ranging from 100 to 400 mg.

The analysis included a total of 245 participants (180 men and 65 women) treated with GSK744 and 29 placebo recipients, with a median age of about 32 years; 20 were people with HIV.

Results

Across the studies there were no drug-related serious adverse events or deaths. 6 people (2%) withdrew early due to adverse events, including 2 events (dizziness and mild rash) judged to be drug-related.

There were 3 serious events not considered related to GSK744 (osteomyelitis or bone marrow inflammation, uterine fibroids, and appendicitis).

Overall, 18% of participants reported any drug-related adverse events other than injection site reactions.

Reactions were more common with GSK744 than with inactive placebo injections.

Most injection-site symptoms (93%) were reported as mild.

There were no severe injection site reactions, no one withdrew for this reason, and all reactions resolved.

Injection site reactions were more common with subcutaneous injection than with intramuscular administration, including pain (86% vs 73%), redness (79% vs 19%), and nodules (79% vs 14%).

Pain and redness after intramuscular injection lasted a median of five days, while nodules after subcutaneous administration lasted a median of 47 days.

No relationship was observed between drug dose and any non-injection site adverse events, lab test abnormalities, electrocardiogram changes, or injection site reactions.

"GSK744as single and repeat oral doses up to 50 mg and [subcutaneous or intramuscular] LAP injections up to 800 mg were well tolerated," the researchers summarised. "All [injection-site reactions] were self-limited and predominantly grade 1."

"This meta-analysis supports the continued clinical development of GSK744 as both oral and LAP formulations," they recommended.